This invention relates generally to methods of inducing a pancreatic endocrine phenotype and function including pancreatic hormone production in a non-endocrine tissue and in particular to methods and pharmaceutical compositions for treating endocrine related disorders.
The endocrine pancreas consists primarily of islet cells that synthesize and secrete the peptide hormone glucagon, insulin, somatostatin and pancreatic polypeptide. Insulin gene expression is restricted to pancreatic islet 6-cells of the mammalian pancreas through control pus mechanisms mediated in part by specific transcription factors. In other cells the insulin, other pancreatic hormones and specific peptidases genes are trancriptionally silent. The homeodomain protein PDX-1 (Pancreatic and Duodenal Homeobox gene-1, also known-as IDX-1, IPF-1, STF-1 or IUF-1) plays a central role in regulating pancreatic islet development and function. PDX-1 is either directly or indirectly involved in islet-cell-specific expression of various genes such as for example insulin, glucagon somatostatin, proinsulin convertase 1/3 (PC 1/3), GLUT-2 and glucokinase. Additionally, PDX-1 mediates insulin gene transcription in response to glucose.
The invention is based in part on the discovery that ectopic expression of pancreatic and duodenal homobox gene 1 (PDX-1) in liver induces the expression of the silent pancreatic hormone genes and the processing machinery, which converts the prohormones into mature biologically active hormones.
The invention provides methods of inducing pancreatic hormone, e.g., insulin, glucagon and somatostatin levels in a subject. In one aspect, the method includes administering to a subject in need thereof a compound which increases PDX expression or activity in an amount sufficient to induce pancreatic hormone production in the subject. In another aspect, the method includes providing a cell capable of expressing a pancreatic hormone, contacting the cell with a compound which increases PDX expression or activity and introducing the cell into a subject, thereby inducing pancreatic hormone production in the subject. Also provided in the invention is a method of treating a pancreatic-related disorder, e.g.,
diabetes in a subject. The method includes administering to a subject a therapeutically effective amount of a compound which increases PDX expression.
In another aspect the invention provides a method of inducing a pancreatic islet gene expression profile in a subject. The method includes administering to a subject in need thereof a compound which increases PDX expression or activity in an amount sufficient to induce pancreatic islet gene expression.
In yet a further aspect of the invention is a method inducing or enhancing a pancreatic islet cell phenotype in a cell. The method includes contacting a cell with compound which increases PDX expression or activity in an amount sufficient to induce or enhance pancreatic islet cell phenotype in said cell.
Also included are pharmaceutical composition that includes a compound which increases PDX expression and a pharmaceutically acceptable carrier.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.